tbuckley/cabot-search huggingface dataset:
Abstract 65: A novel tool for functional characterization of mutations and their response to targeted therapy
Authors: Zohar Barbash, DIkla Haham, Natalie Fillipov-Levy, Limor Cohen, Lea Birnbaum, Shay Rotkopf, Ilona Kifer, Gabi Tarcic
Journal: Cancer Research (2022)

Abstract Genomic profiling of tumors has uncovered staggering amounts of novel alterations, termed variants of uncertain significance (VUS), even in well-studied oncogenes. Strikingly, as the number of sequenced samples increases so does the number of VUS. While the study of alterations identified as VUS has shown that some are inconsequential, it has also been shown that many can cause protein activation and are involved in oncogenicity and resistance to therapy or might serve as novel drug targets. We developed a high-throughput cell-based assay that allows functional annotation of VUS and their sensitivity to different inhibitors. The system quantifies signaling pathway activation using fluorescent imaging coupled with image analysis of cells expressing the mutated protein together with a fluorescently labeled signaling pathway reporter. We show that this method accurately identifies known driver mutations in 10 different oncogenes, including receptor tyrosine kinases and signaling proteins, spanning the four major signaling pathways involved in cancer. We then deployed this system to characterize over 100 different VUS in these genes. We also show that the method correctly recapitulates differential sensitivity of cKIT and EGFR mutations to different inhibitors. Finally, we highlight the importance of concurrent mutations in KRAS which abrogate the response to EGFR inhibitors. Altogether, this system provides significant information both for development of new targeted agents as well as tailoring of optimal treatment for patients. Citation Format: Zohar Barbash, DIkla Haham, Natalie Fillipov-Levy, Limor Cohen, Lea Birnbaum, Shay Rotkopf, Ilona Kifer, Gabi Tarcic. A novel tool for functional characterization of mutations and their response to targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 65.
Abstract 3517: Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor activity
Authors: Jacob S. Lee, Pamela Toy, Gundula Min-Oo, Tony Lee, Patrick Salvo, JeanPhilippe Belzile, Sheila Clancy, Jonathan Nazareno, Mengshu Xu, Weimei Xing, Marilyn Giacomini, Rex Santos, Lance Stapleton, Adele Wang, Vladislava Juric, Scott A. Mitchell, Michelle Kuhne
Journal: Cancer Research (2022)

Abstract Hematopoietic progenitor kinase 1 (HPK1, mitogen-activated kinase kinase kinase kinase 1 [MAP4K1]), a cytosolic STE20 ser/thr kinase from the germinal center family of kinases, regulates the function of diverse immune populations including T cells, B cells, and dendritic cells. In T cells, activated HPK1 regulates T cell receptor (TCR) signaling by phosphorylating the adaptor protein SLP76 on Ser376, which induces the association of SLP76 with 14-3-3 proteins. This SLP76/14-3-3 complex leads to its disassociation from the TCR signalosome, resulting in reduced downstream TCR signaling. The kinase activity of HPK1 is necessary for its regulatory function as mice expressing a mutant kinase-inactive HPK1 demonstrate enhanced T cell activity and superior tumor growth control compared to their WT counterparts. Here we describe a highly potent, selective and orally bioavailable small molecule inhibitor of HPK1 which displays sub-nanomolar HPK1 inhibition, good selectivity against MAP4K family members and oral bioavailability in preclinical animal models. Pharmacological inhibition of HPK1 kinase activity with Gilead’s HPK1 inhibitor compound demonstrates robust inhibition of pSLP76 S376 with concomitant enhancement in T cell activation, proliferation and effector function in in vitro assays. These immune enhancing effects translate into in vivo preclinical tumor models, where treatment with Gilead’s HPK1 inhibitor compound results in heightened T cell activation and effector function and enhanced tumor growth control both as a single agent and in combination with PD-1 blockade. In summary, our data show that Gilead’s HPK1 inhibitor compound is expected to be a selective, orally bioavailable HPK1 inhibitor with potential to combine with checkpoint inhibitors and other immuno-oncology agents. Citation Format: Jacob S. Lee, Pamela Toy, Gundula Min-Oo, Tony Lee, Patrick Salvo, JeanPhilippe Belzile, Sheila Clancy, Jonathan Nazareno, Mengshu Xu, Weimei Xing, Marilyn Giacomini, Rex Santos, Lance Stapleton, Adele Wang, Vladislava Juric, Scott A. Mitchell, Michelle Kuhne. Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3517.
Abstract 388: AI/ML-driven discovery of a novel proteoglycan for precision targeting of ADCs for disruption of stromal barriers and direct anti-tumor activity
Authors: Elizabeth Koch, Max London, Amy Berkley, Allison Nixon, Sean Phippen, Kerry White, Amanda Hanson, Samuel Cooper, Christopher Harvey, Michael Briskin
Journal: Cancer Research (2022)

Abstract Background: While checkpoint inhibitors (CPIs) such as anti-CTLA-4 and anti-PD-1/L1 have demonstrated efficacy in a number of solid tumor indications, those with high stromal presence have been difficult to treat with minimal response observed. We aimed to use a proprietary machine learning/artificial intelligence platform to identify novel stromal targets to relieve this immunosuppressive barrier and increase CPI responsiveness in difficult to treat indications. Methods: Based on bioinformatic analysis using our single cell RNA atlas, we assessed cancer-associated fibroblasts (CAFs)/fibroblastic cells in cancer tissue for identification of novel targets, including proteoglycans. Antibodies were generated by immunization of humanized mice, and lead antibodies were tested for activity in inhibiting cell adhesion and were further characterized for staining of both CAFs as well as tumor cells. ADCs were developed and tested in vitro for selective tumor cell killing. Results: Bioinformatic analysis identified a unique subset of cancer-associated fibroblasts, termed ecmCAFs, which demonstrated selective expression of Collagen Triple Helix Repeat Containing 1 (CTHRC1). This highly-selective expression pattern suggests it may be ideal as a target for alternative modalities, including ADC targeting or specific T cell activation. In addition, we identified that in certain tumor types, such a triple negative breast cancer and pancreatic ductal adenocarcinoma (PDAC), CTHRC1 is also highly expressed by cancer cells within the tumor and shows a more favorable expression profile for ADC targeting when compared to other stromal proteins such as FAP and LRRC15. We have confirmed surface expression and binding of CTHRC1 by our lead antibodies and have observed robust internalization on both human and mouse cancer cell lines. In vitro killing of tumor cells by ADCs and in vivo PD and efficacy will be presented on both ADCs and naked antibodies. Conclusions: We have identified CTHRC1 as a novel proteoglycan expressed by both ecmCAFs and tumor cells that appears to be an ideal target for both direct inhibition of stromal barrier function as well as targeting of cytotoxic payloads as an ADC. CTHRC1 expression is more selective than the classical markers FAP and LRRC15, both of which have been previously developed as ADCs. Citation Format: Elizabeth Koch, Max London, Amy Berkley, Allison Nixon, Sean Phippen, Kerry White, Amanda Hanson, Samuel Cooper, Christopher Harvey, Michael Briskin. AI/ML-driven discovery of a novel proteoglycan for precision targeting of ADCs for disruption of stromal barriers and direct anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 388.
Abstract 2018: Therapeutic benefit of dual ALK and FAK inhibition in neuroblastoma
Authors: Seema Chugh, Jean C. Tien, Jennifer Hon, Pushpinder Singh Bawa, Carson Kenum, Chi Chiang Li, Yunhui Cheng, Andrew D. Delekta, Jae Eun Choi, Rahul Mannan, Yuanyuan Qiao, Rajen Mody, Arul Chinnaiyan
Journal: Cancer Research (2022)

Abstract Neuroblastoma (NB) is the most common extracranial pediatric tumor, and accounts for approximately 12% of cancer-related deaths in children. Though several genomic drivers have been identified, the development of targeted therapy for treating this aggressive pediatric malignancy has yet to be realized. Thus, there exists an urgent need to develop alternative therapeutic strategies for treating aggressive and metastatic NB. One novel approach is to therapeutically target anaplastic lymphoma kinase (ALK) and focal adhesion kinase (FAK), which are multi-functional tyrosine kinases implicated in neural development and play an important role in growth and metastasis of several cancers. Genomic aberrations of ALK such as overexpression, amplifications, and mutations, have been reported in NB. The role of FAK has also been delineated in NB as well as associated with disease metastasis. Using in silico analysis of sequencing data from NB patients procured from Pediatric MI-ONCOSEQ (precision oncology program), we found a cohort of patients that express high ALK and FAK expression. Given the potential roles of ALK and FAK in NB, we evaluated the efficacy of a novel compound ESK440, which is a dual ALK and FAK inhibitor. ESK440 has passed Phase 1 clinical trials in adult patients with solid tumors. It is capable of crossing the blood brain barrier and binds to several mutated forms of ALK, thus making ESK440 an attractive therapeutic candidate for treating NB. A wide panel of NB cancer cell lines were screened with ESK440, and a CellTiter-Glo® Luminescent Cell Viability Assay was used to determine the IC-50s. Our results revealed that NB cells with ALK genomic aberrations (mutations and amplifications) showed low IC-50 values. Further, treatment with ESK440 inhibited ALK and FAK associated signaling pathways. We also observed decreased expression of MYCN. Intriguingly, ESK440 studies in NB xenograft model (NB-1) resulted in tumor regression in treated animals. Altogether, our study has discovered the therapeutic potential of dual ALK and FAK inhibitor in NB, and our findings may provide the foundation for initiating clinical trials targeting this disease in pediatric patients. Citation Format: Seema Chugh, Jean C. Tien, Jennifer Hon, Pushpinder Singh Bawa, Carson Kenum, Chi Chiang Li, Yunhui Cheng, Andrew D. Delekta, Jae Eun Choi, Rahul Mannan, Yuanyuan Qiao, Rajen Mody, Arul Chinnaiyan. Therapeutic benefit of dual ALK and FAK inhibition in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2018.
Multidrug-resistant Enterobacterales infections in abdominal solid organ transplantation
Authors: Benoît Pilmis, Emmanuel Weiss, Anne Scemla, Alban Le Monnier, Paolo Antonio Grossi, Monica A. Slavin, Christian Van Delden, Olivier Lortholary, Catherine Paugam-Burtz, Jean-Ralph Zahar
Journal: Clinical Microbiology and Infection (2022)
Abstract 3571: Prevention of non-small cell lung cancer with kras mutation using a novel peptide vaccine
Authors: Suhe Wang, Zhengyi Cao, Jesse Chen, Janczak Katarzyna, James Baker
Journal: Cancer Research (2022)

Abstract Non-small cell lung cancer (NSCLC) is a significant health issue associated with morbidity and mortality. One of the important findings to emerge in NSCLC is that specific genetic mutations that lead to cancer development occur early in the disease process. Unfortunately, identifying NSCLC at its earliest stages when it is curable has been a challenge even in high risk individuals. These gene mutations, especially those involving the Kras protein, can “drive” the development of NSCLC cancer as they alter the regulation of cell growth or block programmed cell death. Mutations in Kras have been reported in 30% of lung cancer cases and are associated with worse outcomes. This neo-antigen cannot generate effective anti-tumor immunity, suggesting lack of a cellular, cytotoxic immune response to cancer cells on mucosal/epithelial surfaces. No effective therapies specifically targeting mutant Kras have been developed. To overcome poor immunogenicity of neo-antigen, newer adjuvants (NA), biocompatible nanoparticles, were used to enhance immune response. It has been reported NA can produce cytotoxic and mucosal immunity safely in humans. Producing this type of immune response to mutated Kras through immunization could produce a significant anti-tumor effect. In the current study, we first tested NA combined with mutated and wild type (MHC II) Kras peptides vaccine for immunogenicity on the same genetic background as the animals in the inducible tumor model. Our data have demonstrated that NA in combination with multiple Kras peptides can increase CD4+ and CD8+ T cell numbers in the draining lymph node cells and enhance antigen specific TH1 and TH17 responses by luminex and ELISpot to increase the ability of the vaccine to kill tumor cells and elicit long-lasting immune memory. Furthermore, we evaluated anti-tumor efficacy of this vaccine in tetracycline-inducible mouse model with Kras mutation. In this challenge model, vaccinated mice showed higher IFNɤ and IL-17 levels and decreased the tumor incidence significantly compared to PBS or peptides alone group. In conclusion, we have demonstrated the antigen-specific cellular immune responses and mononuclear cell infiltrates correlate with tumor prevention. Our data suggest that this novel vaccine could prevent the development of NSCLC after validation in an appropriate animal model. Citation Format: Suhe Wang, Zhengyi Cao, Jesse Chen, Janczak Katarzyna, James Baker. Prevention of non-small cell lung cancer with kras mutation using a novel peptide vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3571.
Abstract 5565: Analysis of immune landscape in hepatocellular carcinoma patients with MDM2/4 mutations
Authors: Xinjun Wang, Hushan Zhang, Yuan Yang, Hang Du, Jingling Tang
Journal: Cancer Research (2022)

Abstract Background Previous studies indicated that alteration of MDM2/4 was related to poor response even hyper-progressive disease (HPD) to immune checkpoint inhibitors (ICI) therapy. Meanwhile, ICI monotherapy showed low effective rate in hepatocellular carcinoma (HCC), it is still unclear that whether it was associated with HPD-related gene mutation such as MDM2/4. Herein, we analyzed characteristic of MDM2/4 mutation in HCC from tumor immune microenvironment (TIME), to explore the underlying mechanism. Methods Gene mutation of 2615 patients with HCC was analyzed by next generation sequencing (NGS) in 3D Medicines, a laboratory accredited by CAP and Clinical Laboratory Improvement Amendments (CLIA), from Octomber 2017 to May 2020, 68 tumor tissue samples were collected for analysis of TIME, including CD8+ T cells, CD68+HLA-DR+ M1 macrophages and CD68+HLA-DR- M2 macrophages, CD56bright and CD56dim NK cells infiltrated in the tumor tissue, which were detected by multiple fluorescence immunohistochemistry (mICH). Results Among these patients with HCC, 19.54% (511/2615) were mutated in gene MDM2/4, 18.9% (493/2165), 0.7% (18/2165) were MDM2 and MDM4, respectively. The 68 samples were divided into two groups, including group with wild type MDM2/4, and group with MDM2/4 alterations. Analysis of immune cell infiltration revealed that almost all of these immune cells we detected were less infiltrated into tumor tissue of patients with MDM2/4 mutation than without MDM2/4 mutation. What’s more, the most significant difference between patients with and without MDM2/4 alteration was infiltration of CD56dim NK cells (p&amp;lt;0.001). Conclusion The poor response to ICI monotherapy may associated with the high proportion of alteration in gene MDM2/4, which was characterized by low infiltration of immune cells, especially effective NK cells. Citation Format: Xinjun Wang, Hushan Zhang, Yuan Yang, Hang Du, Jingling Tang. Analysis of immune landscape in hepatocellular carcinoma patients with MDM2/4 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5565.
Abstract 949: Novel stilbene compounds inhibit triple-negative breast cancer invasive potential
Authors: Lyndsay V. Rhodes, Kaelyn Julmeus
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive breast subtype of breast cancer that lacks targeted therapies. We have previously identified several novel stilbene compounds that effectively decreased viability of TNBC. Stilbenes are natural defense compounds produced by plants and have been popularized in recent years due to general observed health benefits. Resveratrol, the most widely studied stilbene, has been revealed to possess significant antioxidant and anti-cancer effects. Many stilbenes are classified as phytoestrogens, but unlike estrogens, stilbenes do not appear to negatively impact normal breast tissue or reproductive organ health. Thus, these compounds represent new alternatives for cancer therapeutic development. The focus of this research was to identify stilbene compounds with anti-migration and/or anti-invasive properties in TNBC cells and to determine the mechanism of these inhibitory effects. Two TNBC cell lines, MDA-MB-157 and BT-549, were treated with stilbene compounds at sub-lethal doses and assessed for effects on migration and invasion using transwell assays. Cell morphology changes were evaluated with results suggestive of reversal of epithelial-to-mesenchymal transition (EMT), a key contributor in the metastatic process and a common characteristic of many TNBC cells. Gene expression analysis confirmed stilbene-induced changes of EMT-related genes. These data indicate that stilbenes, like resveratrol and related analogues, reduce cell motility and invasion through regulation of EMT gene expression in TNBC cells. Development of synthetic analogs of natural compounds remains a viable drug development opportunity for new therapeutics. Citation Format: Lyndsay V. Rhodes, Kaelyn Julmeus. Novel stilbene compounds inhibit triple-negative breast cancer invasive potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 949.
Abstract 5102: Correlation analysis of CREBBP mutation with tumor mutation burden and effect of immune checkpoint therapy in bladder cancer
Authors: Abai Xu, Tingting Chen
Journal: Cancer Research (2022)

Abstract Background: CREB-binding protein (CREBBP, hereafter CBP) encoded the protein having intrinsic histone acetyltransferase activity, which stabilized the additional protein interactions with the transcription complex. The mutation of CREBBP has been reported that caused Rubinstein-Taybi syndrome (RTS) and associated with acute myeloid leukemia, but not been studied in bladder cancer (BLCA). Immune checkpoint therapy (ICI) has significantly became one of the primary treatment of BLCA, and Tumor mutation burden (TMB) has been regarded as the most prevalent biomarker to predict immunotherapy. The CREBBP mutation status correlation with TMB and immune response remain unknown. Methods: Whole exome sequencing (WES) data and clinical data of 406 BLCA patients was obtained from the Cancer Genome Altas (TCGA). The mutation data of 206 FFPE tumor samples from Chinese BLCA patients were sequenced by targeted next-generation sequencing (NGS, 3DMed panel). NGS data and clinical data of 192 advanced BLCA patients treated with ICI were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). The association between CREBBP mutation and TMB level in BLCA were explored. Survival analysis was determined by Kaplan-Meier (KM) analysis. Results: In total, The CREBBP mutation frequency was 16.25% (66/406) of BLCA patients in TCGA, 14.56% (30/206) in Chinese cohort and 13.54 (26/192). In Chinese cohort, the alteration frequency of NOTCH signal pathways affected was 48.54% (100/206), in which the highest frequency genes was CREBBP. The TMB level in CREBBP mutant group was higher than wild-type group both in Chinese group (Wilcoxon test, p = 0.001) and MSKCC cohort (Wilcoxon test, p &amp;lt; 0.001). The survival analysis were performed on patients from TCGA cohorts without treatment information and MSKCC BLCA patients treated with ICIs, separately. In TCGA cohort, there are not significantly difference between CREBBP mutation group (n=65) and wild-type group (n=340). While in MSKCC ICIs treatment cohort, the overall survival (OS) of CREBBP mutation group (n=26) were significantly longer than wild-type group (n=166) (median OS, mutation vs wild-type = NE vs 15 months; HR 0.468 [95% CI 0.26-0.84]; P = 0.0431). Conclusion: The CREBBP gene mutation was associated with higher TMB level. Clinical cohort analysis results suggested that CREBBP might be a predictive biomarker of immune checkpoint therapy but not a prognostic factor in BLCA. Citation Format: Abai Xu, Tingting Chen. Correlation analysis of CREBBP mutation with tumor mutation burden and effect of immune checkpoint therapy in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5102.
Abstract 2806: High sensitivity qPCR microsatellite instability detection in FFPE tissue
Authors: Yan Helen Yan, Blake Young, Zhiheng Wang, Adam Yaseen, Alessandro Pinto, David Zhang
Journal: Cancer Research (2022)

Abstract Microsatellite instability (MSI) refers to genetic instability in short nucleotide repeats (e.g., 1-6bp tandem repeats), where a cell comprises a different number of repeats as compared to what was inherited from a progenitor cell. This genetic instability is often observed in tumor cells with impaired mismatch repair (MMR), especially in colorectal cancer (CRC) and endometrial cancer. MSI-high tumors can help identify patients that would benefit from additional genetic testing to diagnose Lynch Syndrome. Additionally, MSI can potentially be used as a biomarker to predict response to treatment with immunotherapy and CRC patients with MSI have a significantly better prognosis compared to those with intact mismatch repair. Here we present the VarTrace® MSI Research qPCR Assay, which enables high sensitivity detection of microsatellite instability. The assay uses NuProbe’s PCR-based Blocker Displacement Amplification (BDA) technology to enable the selective amplification of MSI unstable alleles with 1% analytical limit of detection. The assay is intended for the qualitative detection of mutations in 5 MSI loci (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) without the need of matched normal, and reports MSI-high (MSI-H), MSI-low (MSI-L) and Microsatellite Stable (MSS). Analytical validation of the assay has been completed on Horizon MSI/MSS formalin-fixed, paraffin-embedded (FFPE) DNA reference standard, SeraCare MSI AF5% reference panel mix, and 50 CRC FFPE samples. One FFPE section with as little as 2ng of input DNA is enough for this assay. The high sensitivity potentially allows for the detection of MSI status in liquid biopsy. Citation Format: Yan Helen Yan, Blake Young, Zhiheng Wang, Adam Yaseen, Alessandro Pinto, David Zhang. High sensitivity qPCR microsatellite instability detection in FFPE tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2806.